ESMO 2023: Evolving Frontline Treatment Paradigms in Advanced Renal Cell Carcinoma

(UroToday.com) The 2023 ESMO annual meeting included a session on optimizing overall survival in advanced renal cancer, featuring a presentation by Dr. Toni Choueiri discussing evolving frontline treatment paradigms. Dr. Choueiri started by highlighting the key first-line combination therapy trials in advanced clear cell RCC:

The first key IO + IO combination therapy trial (PD-1 + CTLA4 inhibitor) in this disease space was the CheckMate 214 trial,¹ initially presented six years ago at ESMO 2017. This trial randomized treatment naïve patients to nivolumab + ipilimumab versus sunitinib, with the following trial design:
With now extended follow-up, the combination of nivolumab + ipilimumab has shown a durable and significant OS and PFS benefit compared to sunitinib in intermediate and poor risk patients:²
Moving to the IO + VEGF combination trials, Dr. Choueiri notes that there is a renal cell carcinoma-specific “cancer immunity cycle” that provides the biology for combining these two classes of treatment, specifically with T-cell mediated cancer cell killing being enhanced through reversal of VEGF-mediated immunosuppression:
Dr. Choueiri noted that we have mature, durable, and important long-term OS, PFS, and objective response rate outcomes for three key doublet trials:

KEYNOTE-426 (pembrolizumab + axitinib versus sunitinib):
CLEAR (pembrolizumab + lenvatinib versus sunitinib):
and CheckMate-9ER (nivolumab + cabozantinib versus sunitinib):
So, can we compare across trials? Dr. Choueiri notes that the baseline characteristics in the first-line mRCC phase 3 trials are very different:

When looking at the quality of life data across these three trials (versus sunitinib), we see that there was improved quality of life (FKSI-19) for nivolumab +ipilimumab in CheckMate 214, improved quality of life (FKSI-19/DRSS) for nivolumab + cabozantinib in CheckMate-9ER, and similar quality of life (QLQ-C30/FKSI-DRS) for pembrolizumab versus axitinib in KEYNOTE-426. However, the caveats are that (i) there were different instruments used across studies, (ii) different time points were assessed, and (iii) compliance rates varied across trials.

Dr. Choueiri then discussed three “special populations” in first line treatment of metastatic RCC, starting with favorable IMDC risk group patients, which make up ~20% of metastatic patients. When looking at the 60 month response data from CheckMate 214, objective response rate actually favored sunitinib in these favorable risk patients, whereas there was a benefit to nivolumab + ipilimumab for complete response rate, median duration of response, and treatment-free interval:
In a recent FDA pooled analysis of frontline combination treatment survival benefits by risk groups in metastatic RCC,³ Lee and colleagues found that IO + TKI combinations have yet to demonstrate an OS benefit in favorable-risk (HR 1.24, 95% CI 0.86 to 1.78) patients despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64, 95% CI 0.55 to 0.75) patients. However, IO + TKI combination therapy has demonstrated a PFS benefit for both the favorable-risk (HR 0.63, 95% CI: 0.50 to 0.79) and the intermediate/poor-risk (HR 0.52, 95% CI 0.45 to 0.60) group:
Secondly, patients with sarcomatoid differentiation comprise ~5-15% of patients. In a sub-analysis of CheckMate 214, intermediate and poor risk patients with sarcomatoid features, had a significant benefit to receiving nivolumab + ipilimumab as compared to sunitinib, with both an OS and PFS benefit:

Indeed, sarcomatoid RCC tumors have an immune-inflamed phenotype that leads to activation of immune pathways, increased expression of APM genes, increased cytotoxic immune infiltration, high PD-L1 on tumor cells, and upregulated H3K27ac peaks enriched for genes of immune response and inflammation.

Third, Dr. Choueiri discussed papillary RCC patients, which make up the second most common histology after clear cell. The PAPMET SWOG trial randomized in a 1:1:1:1 fashion to receive either sunitinib 50 mg oral daily (6-week cycles: 4 weeks on/2 weeks off), cabozantinib 60 mg oral daily, crizotinib 250 mg oral twice daily, or savolitinib 600 mg oral daily.⁴ Median PFS was significantly higher with cabozantinib relative to sunitinib (HR 0.60, 95% CI 0.37-0.97):
A second study in this disease space was the SAVOIR trial with MET-driven therapy with savolitinib. Although not statistically significant, this trial showed a possible benefit of savolitinib versus sunitinib for PFS (HR 0.71, 95% CI 0.37 to 1.36) and OS (HR 0.51, 95% CI 0.21 to 1.17). Additionally, the CALYPSO trial assessed the efficacy of savolitinib + durvalumab versus savolitinib monotherapy in MET-driven papillary RCC. This trial found that the combination of savolitinib + durvalumab had an acceptable tolerability and safety profile in the exploratory MET-drive subgroup:
Dr. Choueiri highlighted that one trial actively recruiting is the SAMETA trial, which is randomizing patients with metastatic papillary RCC to (Arm A) savolitinib + durvalumab vs (Arm B) sunitinib vs (Arm C) durvalumab monotherapy, with a primary endpoint of PFS:
Dr. Choueiri then shifted to discuss the possibility of triplet approaches, specifically the recently presented and published COSMIC-313 trial:⁵

COSMIC-313 reached its primary endpoint of improved PFS with the triplet therapy of cabozantinib + nivolumab + ipilimumab versus nivolumab + ipilimumab alone, with a HR of 0.73, 95% CI 0.57-0.94:
What is interesting, however, is that the PFS benefit appears to be primarily driven by the intermediate risk group (HR 0.63, 95% CI 0.47-0.85) rather than the poor risk group (HR 1.04, 95% CI 0.65-1.69):
Notably, triplet therapy was associated with increased toxicity, specifically grade 3-4 adverse events affected 73% in the triplet therapy group as compared to 41% in the nivolumab + ipilimumab group. Putting COSMIC-313 into perspective, there are several key points:

• This is the first trial versus a modern doublet control (nivolumab + ipilimumab)
• It is the first positive triplet trial for PFS. The curves separate early and stay separated, there is low risk of progressive disease, and there is higher tumor response with triplet therapy
• However, responses are marginally better and there are few complete response, with no overall survival benefit at the first interim analysis. Additionally, there is more toxicity, treatment discontinuation, and need for steroids

There are several ongoing triplet therapy trials in the first line setting:

With regards to non-IO approaches, Dr. Choueiri highlighted the CABOSUN trial assessing cabozantinib,⁶ which is approved in first line metastatic RCC based on randomized phase 2 data showing a PFS benefit and improved objective response rate. Additionally, there is the LITESPARK-003 trial, which tested VEGF TKI + HIF-2 inhibitor and will be presented as a late breaking abstract at ESMO 2023.

Dr. Choueiri concluded his presentation discussing evolving frontline treatment paradigms with the following take-home points:

• There is a wealth of evidence of different combinations for the first line treatment of metastatic (clear cell) RCC: IO + VEGF vs IO + IO
• Patients in your clinic do not always reflect the trial population and real world data collection is important
• There are many factors that may influence a physician’s choice of sequential treatment and personalization of care, including availability of options, efficacy, safety, quality of life, prior treatment, comorbidities (ie. cardiovascular, autoimmune disease), and cost
• Favorable intermediate risk therapy remains undefined, however, a case can be made for IO + IO, IO + VEGF, or VEGF monotherapy, or observation (indolent disease). Dr. Choueiri personally uses IO + VEGF for these patients
• For patients with sarcomatoid features, nivolumab + ipilimumab should be the standard of care
• We are finally seeing dedicated RCTs in the non-clear cell MET-driven papillary RCC population
• Biomarkers today all remain experimental in metastatic RCC
• The post adjuvant IO space is emerging, with the first line choice in metastatic RCC becoming more complicated

Dr. Choueiri’s first line treatment algorithm for metastatic RCC is as follows:
Presented by: Toni K. Choueiri, MD, Dana-Farber Cancer Institute, Boston, MA

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.

References:

1. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med 2018;378(14):1277-1290.
2. Albiges L, Tannir NM, Burotto M, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: Extended 4-year follow-up of the phase III CheckMate 214 trial. ESMO Open 2020 Nov;5(6):e001079.
3. Lee D, Gittleman H, Weinstock C, et al. A U.S. Food and Drug Administration-pooled Analysis of Frontline Combination Treatment Survival Benefits by Risk Groups in Metastatic Renal Cell Carcinoma. Eur Urol. 2023 Oct;84(4):373-378.
4. Pal S, Tangen C, Thompson Jr E, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial." The Lancet. 2021. S0140-6736(21)00152-5.
5. Choueiri TK, Powles T, Albiges, et al. Cabozantinib plus Nivolumab and Ipilimumab in Renal Cell Carcinoma. N Engl J Med. 2023 May 11;388(19):1767-1778.
6. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The Alliance A031203 CABOSUN Trial. J Clin Oncol 2017;35(6):591-597.